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MolCell Mega Class > ANDREASSEN 4 > Flashcards

ANDREASSEN 4 Flashcards

1
Q

The DNA damage response (DDR) is critical for maintaining _________ and preventing human diseases such as _________.

A

genome stability, cancer

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2
Q

The three major prongs of the DNA damage response are:

A

Cell cycle (checkpoint) arrest, DNA repair, Apoptosis

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3
Q

List three key functions of the DDR

A

Detecting (sensing) DNA damage, Mediating subsequent signaling that arrests the cell cycle (as appropriate), Coordinately mediating signals that recruit and regulate DNA repair proteins.

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4
Q

The term “DNA damage checkpoint” can refer to the arrest of a particular process such as _________, or to ________ in response to DNA damage.

A

a block to the firing of new origins, cell cycle arrest at a particular stage (like G2)

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5
Q

Besides its role in maintaining genome stability, the DNA damage response is also important to _________ and _________.

A

cancer genetics, cancer therapy

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6
Q

DNA-PK, ATM, and ATR are all _________ which are key transducers in DNA damage responses.

A

PI3K-related protein kinases

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7
Q

ATM and ATR are sometimes called “__________” because deficiency for either of them perturbs certain checkpoints.

A

checkpoint kinases

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8
Q

ATR and ATM have evolved to mediate and coordinate the response to _________ and _________, respectively.

A

replication stress, DSBs (double-strand breaks)

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9
Q

Replication stress impedes _________ and can lead to _________.

A

DNA replication, fork collapse

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10
Q

Fork collapse blocks _________ and can yield _________.

A

proliferation, DSBs

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11
Q

ATR promotes DNA replication via the _________ checkpoint.

A

intra S

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12
Q

Besides promoting DNA replication, ATR also recruits _________ necessary to restart stalled replication forks.

A

HR (homologous recombination) proteins

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13
Q

DSBs must be repaired prior to _________ to ensure _________.

A

mitotic entry, chromosome integrity

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14
Q

ATM recruits _________ necessary to repair DSBs.

A

HR proteins

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15
Q

List three examples of replication stress-inducing agents

A

UV-C, HU (hydroxyurea), MMC (mitomycin C)

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16
Q

List two examples of DSB-inducing agents

A

IR (ionizing radiation), Topo II inhibitors

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17
Q

The sensor for DSBs is the _________ complex.

A

MRN (MRE11/Rad50/NBS1)

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18
Q

List three sensors for replication stress

A

RPA, Rad17, H2AX

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19
Q

ATM and ATR phosphorylate proteins with distinct roles in DNA damage responses, including:

A

Partner kinases – Chk1/Chk2, Sensors of DNA damage – NBS1, RPA, Rad9, Damage signaling – H2AX, BRCA1, Repair proteins – BLM, FANCI, Apoptosis/G1-S checkpoint – p53

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20
Q

The partner checkpoint kinases for ATM and ATR are _________ and _________, respectively.

A

CHK2, CHK1

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21
Q

The concept of cell cycle checkpoints was established by _________ and _________ in _________.

A

Hartwell, Weinert, 1989

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22
Q

Cell cycle checkpoints act to ensure the _________ of cell cycle events.

A

order

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23
Q

Potential consequences of a defect in checkpoints include _________, _________, and _________.

A

cell death, increased mutagenesis, infidelity in chromosome segregation

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24
Q

DNA damage can cause checkpoint-dependent arrest of the cell cycle at the _________, within _________, and at _________ prior to mitotic entry.

A

G1-S transition, S phase (intra-S), G2

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25
Q

Cell cycle arrest in response to DNA damage is mediated by _________ or _________ depending on the type of damage via control of _________.

A

ATM, ATR, cyclin-dependent kinases (CDKs)

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26
Q

The G1 DNA damage checkpoint acts at the _________ restriction point.

A

Rb-dependent

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27
Q

Seminal work on p53 and pRb was critical for understanding:

A

The role of tumor suppressors, Cell cycle control, Cell cycle checkpoints, DNA damage responses, Viral oncogenesis

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28
Q

The MRN complex senses a _________ in chromatin and activates _________ ATM.

A

conformational change, dimeric

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29
Q

Activated ATM phosphorylates many substrates including its partner, _________.

A

Chk2

30
Q

ATM-dependent phosphorylation of _________ (in the MRN complex) recruits/activates more ATM.

A

NBS1

31
Q

ATM-dependent phosphorylation of NBS1 is a _________ mechanism that amplifies ATM-dependent signaling.

A

feedback

32
Q

DNA damage response signaling events provide access of _________ to compacted chromatin.

A

DNA repair factors

33
Q

A critical ATM or ATR target in DSB and replication stress, respectively, is a variant histone ______ (______) present in nucleosomes.

A

H2A, H2AX

34
Q

MDC1 recruitment is the basis for subsequent _________ of H2A and H2AX, and further recruitment of DNA repair factors.

A

polyubiquitination

35
Q

RNF8 mediates ubiquitination of ______ (and/or ______).

A

H2A, H1

36
Q

Writers establish the _________ (acetylation, methylation, phosphorylation, or ubiquitination) on histones.

A

histone mark

37
Q

_________ is a “writer” of phosphorylation, while _________ is a polyubiquitin “writer.”

A

ATM, RNF8

38
Q

Readers recognize and bind to histones modified with a particular _________ (acetylation, methylation, phosphorylation, or ubiquitination).

A

mark

39
Q

_________ is a “reader” of H2AX phosphorylation, and _________ is a “reader” of histone ubiquitination.

A

MDC1, RAP80

40
Q

K48-linked polyubiquitination targets proteins for _________.

A

proteasome-mediated degradation

41
Q

K63-linked polyubiquitination is involved in the recruitment of _________.

A

DDR proteins

42
Q

Signaling through gamma-H2AX and MDC1 coordinates HR: _________ (commitment) and _________ (initiation).

A

end resection, strand invasion

43
Q

53BP1 recognizes DNA damage-induced modifications of histones ______ and ______.

A

H2A, H4

44
Q

53BP1 promotes _________.

A

NHEJ (non-homologous end joining)

45
Q

PTIP and RIF1 block _________ (and HR), which permits binding of ______ proteins and ______ at the damage site to initiate NHEJ.

A

end resection, Ku, DNA-PK

46
Q

Potential consequences of a defect in checkpoints include cell death, increased _______, and infidelity in chromosome segregation.

A

mutagenesis

47
Q

Work with Xenopus extracts suggests that _______ at the fork continue to spool out ssDNA when damage is encountered.

A

helicases

48
Q

The 9-1-1 complex is a _______(shape) that slides until it encounters damage.

A

ring

49
Q

Among the chemical inhibitors for DNA-PK, ATM, or ATR, _______ inhibitors look most promising and may be effective as a monotherapy.

A

ATR

50
Q

P21 blocks CDK2 cyclin E activity at the _______ transition.

A

G1-S

51
Q

The release of _______ allows various cell cycle-related factors to be transcribed, particularly replication or S phase factors.

A

E2F

52
Q

Work that focused on p53 and pRb was critical in understanding the function of _______.

A

tumor suppressors

53
Q

ATM activates its sensor _______ in response to double-strand breaks.

A

MRN

54
Q

Ubiquitin conjugates have a diverse set of functions in cellular signaling, including _______, which is most important for transcriptional regulation.

A

monoubiquitination

55
Q

The MRN complex is the sensor for ATM, and one of its components, _______, is an enzyme involved in end resection.

A

MRE11

56
Q

___________ is a process that occurs at double-strand breaks and involves the removal of nucleotides from the 5’ ends of the break to create 3’ single-strand overhangs. These overhangs are necessary for homologous recombination to occur.

A

End resection

57
Q

True or False: The fact that the MRN complex is involved in both sensing damage and end resection suggests that these two processes are closely linked.

A

True

58
Q

ATR ___________ a variety of target proteins that are involved in the DNA damage response, including checkpoint activation, DNA repair, and apoptosis.

A

phosphorylates

59
Q

_______ is an example of an effector of apoptosis in the DNA damage response.

A

FANCI

60
Q

FANCI is a protein that is involved in the Fanconi anemia pathway, which is a DNA repair pathway that is important for repairing ________________.

A

interstrand crosslinks

61
Q

The decision between repairing a double-strand break by non-homologous end joining or homologous recombination may be influenced by the local _______ environment.

A

chromatin

62
Q

The 9-1-1 complex is made up of three proteins: Rad9, _____, and Hus1.

A

Rad1

63
Q

Fork collapse occurs when the replication fork, the structure that carries out DNA replication, encounters a _______ in the DNA template.

A

lesion

64
Q

When fork collapse occurs, DNA replication is ______, and this can lead to cell cycle arrest or cell death.

A

halted

65
Q

_______ is a protein that is involved in disassembling the displacement loop if it does not find proper homology during homologous recombination.

A

BLM

66
Q

During homologous recombination, a __________ loop (D-loop) is formed.

A

displacement

67
Q

BLM is thought to help disassemble the ________ if it does not find proper homology with the template. This helps to prevent the formation of non-homologous recombination products, which can lead to genomic instability.

A

D-loop

68
Q

Check1 phosphorylates CDC25A, leading to its _______, and thereby maintaining the inhibitory phosphorylation on CDK2.

A

degradation

69
Q

True or False: CDK2 is a CDK that is involved in promoting the transition from G1 to S phase.

A

True

70
Q

Ataxia telangiectasia and Nijmegen breakage syndrome are both rare genetic disorders that are characterized by a defect in the _______________.

A

DNA damage response (DDR)

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